Pharmaceuticals with low solubility in water cause formulation problems due to their poor rate and extent of dissolution in aqueous media (including gastrointestinal fluids), which results in low absorption into systemic circulation after oral ingestion.
Examples of drugs with low solubility in water are some substituted dihydropyridine compounds, such as nifedipine, felodipine, ninodipine, isradipine, nitrendipine, nicardipine, niludipine, nisoldipine, and amlodipine. These compounds are classified as calcium antagonists, which are widely used for the treatment of cardiovascular disorders such as hypertension.
In order to make a composition containing such a drug that will enable maximum absorption from the gastro-intestinal tract, it is necessary to incorporate in the composition a feature that increases the solubility of the drug to enable it to dissolve in the gastrointestinal fluids.
Several ways to increase the solubility have been described in prior literature. One way is described in U.S. Pat. No. 4,673,564, wherein nicardipine is used in its amorphous form in order to obtain increased dissolution and absorption. British patent 1456618 discloses improving the dissolution and absorption of nifedipine by preparation of a solid solution of nifedipine in polyethylene glycol in the presence of a surface active agent.
U.S. Pat. No. 4,412,986 discloses improving the dissolution and absorption of nifedipine by preparing a co-precipitate with a water-soluble polymer.
A feature that increases the solubility of a drug and thereby increases the extent of absorption will generally also increase the rate of absorption of the drug. If a drug is absorbed rapidly, and particularly if it is also eliminated rapidly, it becomes necessary to administer the drug frequently (i.e. several times per day) in order to maintain uniform blood levels. This is an undesirable situation, as frequent dosing is inconvenient for the patient and may lead to noncompliance by the patient.
To overcome this problem, it is necessary to include in the composition, in addition to a first feature to increase solubility of the drug, a second feature to slow down and control the rate at which the drug is released from the composition and made available for dissolution and absorption. A composition with such a feature is referred to in the trade as "extended release" or "controlled release".
The prior literature discloses numerous ways to make extended release compositions which slow-down and control the rate of dissolution and absorption of a drug. Such formulations usually include a substance such as a wax, fatty material, or polymer which causes the composition (usually in the form of a tablet) to erode or dissolve slowly in gastrointestinal fluids thereby slowly releasing the drug contained in the composition.
Especially preferred substances to slow-down the dissolution are hydrophillic gel-forming polymers (usually water-soluble cellulose derivatives). When a composition containing sufficient quantity of such a polymer is ingested and comes into contact with the gastrointestinal fluids, the hydrophillic gel-forming polymer nearest the surface of the composition hydrates to form a viscous gel layer around the surface of the solid mass. Because of the high viscosity, the viscous layer dissolves away only gradually, exposing the material below to the same process. The mass thus dissolves away only slowly, thereby slowly releasing the active ingredient into the gastrointestinal fluid.
In order to produce an extended release composition of a drug having very low solubility in water, it is necessary to have one feature as aforesaid to increase the solubility and a second feature as aforesaid to slow down and control the rate of dissolution.
The prior art also discloses numerous compositions which include a feature of each type to achieve extended release of a drug having low solubility in water.
European patent application 0557-244-A1 discloses compositions which contain nifedipine which has been micronized to small crystals to increase solubility, along with a hydrophillic gel-forming polymer to slow-down and control the rate of dissolution and absorption from the composition. A problem with the compositions disclosed in this patent is the smallest size to which nifedipine can be micronized using conventional equipment is about 1 micron, and this particle size is still not small enough to enable full dissolution and absorption of the nifedipine. Moreover, unless the crystal size is carefully controlled to be the same in every batch of tablets, release characteristics may vary from batch to batch.
U.S. Pat. No. 4,765,989 discloses extended release formulations of nifedipine in the form of an osmotic device, which is relatively difficult and expensive to manufacture.
Accordingly, it is the object of this invention to provide an extended release composition for oral administration of a drug having low solubility which can be manufactured by simple and inexpensive techniques, which does not require micronization of the drug.
It is a further object to provide an extended release composition for oral administration of a drug having low solubility for which the dissolution and absorption characteristics of the compositions are not affected by the crystal form or the particle size distribution of the drug used to make the composition.